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Editorials
Nonetheless, this leads to questions about the mecha- nisms underlying gender-specific differences in develop- mental growth and iron handling in infancy. Iron absorption and iron utilization for erythropoiesis are known to be affected by genetic polymorphisms in different iron metab- olism and erythropoietic genes.2,16 Apart from the descrip- tion of sex-linked anemia in mice and males,1 no specific genetic defects with higher prevalence in females have been described. One might also speculate that cultural differences in feeding procedures between boys and girls or dietary additives in addition to breast feeding which impact on iron bioavailability, may play a role in this setting. It could also be that there is a higher driving force of iron to be incorpo- rated into muscle tissue in boys than in girls, although this would be surprising at this early stage of development. The latter is believed to be rather driven by sex-specific effects of hormones which would not be evident in infancy. Later on in life, this may become more relevant, because testos- terone promotes muscular development whereas estrogens have a positive effect on inflammatory pathways which may negatively impact on dietary iron absorption.7 The same also holds true for hormonal effects on hepcidin expression, which is reduced by testosterone but likewise only becomes important in adolescence. Differences in the prevalence of infections with associated impairment of
Figure 1. Factors impacting on iron availability and absorption for infants. Dietary iron is absorbed in the duodenum. The bioavailability and quantitative absorption of iron are dependent on the one hand by the molecular/heme iron content of the diet and on the other hand on the concentration of hepcidin. The latter blocks the transfer of iron from the duodenal enterocyte to the circula- tion, which is a prerequisite for iron availability for cells and tissues. Among other factors, hepcidin expres- sion is stimulated by infection and inflammation, inhibited by iron defi- ciency, anemia and hypoxia, and can be influenced by genetic polymor- phisms of iron metabolism genes in either direction. It is anticipated that efficient incorporation of the metal by infants is positively associated with promotion of growth and mental development.
dietary iron absorption also do not appear to account for this because fewer females than males were affected by infections. Another issue could arise from sex-specific dif- ferences in intestinal infestation with hookworms which aggravates iron losses by duodenal bleeding. Nonetheless, it is also plausible that more sustained growth is independ- ent of iron absorption, meaning that iron deficiency is the consequence, and not the cause, of growth that is actually driven by other factors. Thus, the issue of sex-specific dif- ferences in iron handling and putative iron-mediated growth promotion remains a matter of speculation which should be addressed in future prospective trials.
Not surprisingly, the authors15 also found that hepcidin levels are much affected by markers of inflammation, namely C-reactive protein (CRP), but also by seasonality, both of which point to a role for infections in their impact on hepcidin levels. This observation generates new knowl- edge which can help predict the optimal time frame for iron substitutions; this could include recommending those months with the lowest seasonal burden of infections as this would increase efficacy or iron absorption and reduce the risk of an increased incidence or unfavorable course of infections. Moreover, iron administration has been shown to be quite safe when preventive measures for reducing the burden of infectious diseases are undertaken. A recent
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haematologica | 2019; 104(8)